A method for preparation of the fungicidal active compound Azoxystrobin is described in International patent publication no. WO 98/18767 wherein water is used as the only reaction medium. However, the process provides relatively low yields and requires long reaction time. To increase the yield potassium fluoride is added to the reaction mixture but potassium fluoride is highly toxic and corrosive to metals and therefore undesirable for large scale application. As seen from the results provided for in WO 98/18767 high production yields of azoxystrobin without using potassium fluoride are only obtainable by substituting water as reaction medium with an organic solvent such as toluene. On laboratory scale, high yields of azoxystrobin have also been provided when conducting the reaction as a melt i.e. without reaction medium. However, this procedure is non-advantageous at large production scale due to both difficulties in stirring of the melt, but also difficult to solubilize the organic compounds i.e. starting materials and products during purification which results in low yields.
The use of 1,4-diazabicyclo[2.2.2]octane (referred to as DABCO) as a catalyst in the preparation of asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives is disclosed in International patent publication no. WO 2001/72719. Use of DABCO as a catalyst enhances the yield and reduces the reaction time. The process is stated to be carried out in an organic solvent. However, the process may also be conducted in an aqueous two-phase system in which it is said to be advantageous to remove the water again during the reaction. Suitable co-solvents for use in such an aqueous two-phase system are said to be solvents which are at least partially water immiscible.
Using a low catalytic loading of DABCO is described in International patent publication no. WO 2006/114572 when producing asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives. The process is preferably carried out in an organic solvent. Again it is stated that the process may also be conducted in an aqueous two-phase system in which it is advantageous to remove the water during the reaction. Suitable co-solvents for use in such an aqueous two-phase system are solvents which are at least partially water immiscible.
Quinuclidine-based or 3-substituted N-methyl pyrrolidine based compounds has been described in International patent publication no. WO 2008/043977 as successful catalysts used in producing asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives. The process described is preferably carried out in an organic solvent, but the process may also be conducted in an aqueous two-phase system in which it is advantageous to remove the water during the reaction. Suitable co-solvents for use in such an aqueous two-phase system are solvents which are at least partially water immiscible.
An alternative method for producing azoxystrobin is described in International patent publication no. WO 2008/075341. The process comprises a 4-step process in which the first step comprise reacting a phenol-derivative with a base in an organic solvent to obtain a phenolate salt, wherein water is removed from the reaction mixture during the reaction. The second and third step comprises adding the aromatic substrate to the reaction mixture and thereby applying heat to the mixture. The final and fourth step, comprise removal of the solvent and isolating and purifying the substrate.
In United States patent application published as US 2010/0179320-A1 yet another alternative process is disclosed for the manufacture of azoxystrobin. This process involves a formylation step of an azoxystrobin intermediate in the presence of a Lewis acid followed by a methylation step.